INTRODUCTION

The last 25 years have seen remarkable progress in the development of multiple sclerosis (MS) treatments ^[1,2]. Although many therapies employing different mechanisms of action are available for relapsing forms of MS (RMS), therapies proven to be effective for progressive RMS are limited. Therapies intended to enhance remyelination have yet to receive regulatory approval and other strategies directed at enhancing recovery from chronic injury have yet to show benefit. Therefore, great unmet needs persist in MS both for treatments that can arrest progressive disability worsening and restore function following central nervous system (CNS) injury. This purpose of this review is two-fold. First, a major change in the treatment philosophy of relapsing RMS is underway. Second, this review will showcase MS therapies that are currently being evaluated in clinical trials. 

A SEA CHANGE IN THE MULTIPLE SCLEROSIS TREATMENT ALGORITHM

MS disease modifying agents are commonly divided into drugs of moderate effectiveness, also termed platform therapies, and high efficacy agent treatments (HEATs). Two strategies were proposed for MS treatment: first, the treat-to-target or tiered escalation approach that begins with lower initial treatment efficacy (LITE) and reserves HEAT for breakthrough disease and second, high efficacy frontline treatment (HEFT) that begins with HEAT early in the disease course. LITE involves initiation of treatment with drugs such as interferons, glatiramer, teriflunomide or fumarates, careful monitoring of the treatment response, and switching to HEAT (natalizumab, anti-CD20 monoclonal antibodies, alemtuzumab, S1P receptor modulators or cladribine) when ongoing disease activity or progressive disability becomes apparent. This approach was driven by safety concerns related to two earlier HEAT therapies: mitoxantrone, which can cause cardiac toxicity and leukemia, and natalizumab which can cause progressive multifocal leukoencephalopathy. The development of risk mitigation strategies for natalizumab and HEATs with more favorable safety profiles such as B-cell-depleting treatments allows for potential use of HEAT early in RMS.

Whereas LITE was the dominant treatment strategy in MS for the last 2 decades, accumulating data from both relatively short-term randomized trials ^[3–7] and results from population-based studies suggest that HEFT provides greater long-term benefit to MS patients ^{[8–15,16▪]}. However, definite conclusions about whether either LITE or HEFT is superior to the other requires head-to-head comparison of these therapeutic strategies in prospective randomized controlled trials. Both the Traditional verses Early Aggressive Therapy for MS trial (TREAT-MS, NCT03500328) and the Determining the Effectiveness of Early Intensive verses Escalation Approaches for the Treatment of Relapsing-remitting MS trial (DELIVER-MS, NCT03535298) are designed to address this question. The primary outcomes are disability progression for TREAT-MS and brain volume loss for DELIVER-MS. Hopefully, these studies will yield consistent results. For now, available data provide some evidence for wider use of HEFT. HEFT offers a therapeutic approach of choosing highly potent therapies at the earliest stages of the disease to capitalize on a theoretical window of opportunity for maximal anti-inflammatory benefit. In contrast, LITE embodies a fix-on-fail philosophy that guarantees irreversible injury for at least some patients.

NEW TREATMENTS IN DEVELOPMENT FOR MULTIPLE SCLEROSIS

Bruton's tyrosine kinase inhibitors

Bruton's tyrosine kinase (BTK) is a cytoplasmic Tec family kinase expressed in all hematopoietic cell lines except for T cells and terminally differentiated plasma cells ^[17,18] (Table 1). BTK is a critical signaling node for peripheral myeloid cells, B cells and CNS microglia. B-cell receptor activation results in intracellular signaling through this kinase with downstream transcriptional regulation governing diverse processes including chemotaxis, trafficking, adhesion, maturation, antibody production and cytokine secretion ^[19]. Inhibition of BTKs is a proved treatment for lymphoma and is under investigation in diverse autoimmune disorders ^[20]. As small molecules, BTK inhibitors (BTKIs) could have advantages over biologics since they are less likely to trigger antibody mediated responses and have the potential for CNS penetrance. Many BTKIs were developed to covalently bind their receptor thereby reducing the steady-state concentration needed for pharmacologic effect. Additional factors to consider are target specificity for BTK relative to other tyrosine kinases and the degree of CNS penetrance.

Evobrutinib was the first BTKI to show therapeutic potential in a phase 2 study in RMS ^[21] and is now being investigated in twinned phase 3 study (NCT04338022, NCT04338061). Tolebrutinib was developed to be a CNS penetrant BTKI ^[22] and showed activity on gadolinium-DPTA lesion formation in RMS ^[23▪]. Three phase 3 trials with tolebrutinib are underway in RMS, primary progressive MS (PPMS) and secondary progressive MS (SPMS) (NCT04879628, NCT04544449, NCT04411641). Fenebrutinib is a peripherally acting, reversibly binding BTKI that is under investigation in twinned phase 3 studies in RMS as well as a phase 3 study in PPMS (NCT04586023, NCT04586010, NCT04544449). Remibrutinib is a peripherally acting, covalent binding BTKI being compared head-to-head versus teriflunomide in a phase 3 study in RMS (NCT05156281). Orelabrutinib is a CNS penetrant BTKI under investigation in a phase 2 study, placebo-controlled trial in RMS (NCT04711148). Several other BTKIs are being considered for clinical trials in MS including two CNS penetrant molecules GB5121 and GB7208 from Gossamer Bio and BIIB091, a peripherally acting BTKI from Biogen. Clearly with so many BTKIs in development, differentiating between these products will be challenging if efficacy and safety profiles for the more peripherally acting BTKIs are similar. The CNS penetrant BTKIs have a potential advantage over the peripherally acting products in that the CNS penetrant BTKis could interact directly with microglial cells. Whether modulation of microglial activation is beneficial in MS is unknown but hypothetically could be important especially for progressive RMS.

Myelin repair

Myelin repair offers hope for restoration of deficits caused by MS demyelination. Histopathology suggests that oligodendroglial precursor cells are present in MS plaques but are unable to remyelinate due to inhibitory signals ^[24] (Table 1). Stimulating oligodendrocyte precursor cells (OPCs) to remyelinate denuded axons could restore saltatory axonal conduction thereby potentially reversing conduction block associated neurological deficits and promoting neuronal survival through renewed trophic support of previously demyelinated axons. Strategies to promote remyelination include overcoming inhibitory signals, stimulating OPC differentiation or providing cofactors for myelin forming enzymes. Opicinumab is a monoclonal antibody directed against leucine rich repeat and Immunoglobin-like domain-containing protein 1 (LINGO-1), an inhibitory signaling molecule that prevents remyelination. Three opicinumab clinical trials proved unsuccessful and further development seems doubtful ^[25,26]. Similarly disappointing results were reported for elezanumab, an inhibitor of repulsive guidance molecule A, another inhibitory factor for myelination and axonal sprouting ^[27]. A phase 1 study was conducted for RHIgM22a, a putative myelin inducing monoclonal antibody, that although detectable in cerebrospinal fluid, showed no discernible effect on gadolinium enhancing lesions ^[28]. Small molecules with putative myelin repair properties also were investigated. MD-1003, pharmaceutical grade, high-dose, biotin is a cofactor for acetyl-CoA carboxylases that are involved in fatty acid metabolism and underlie myelin production as well as carboxylases that generate intermediates for the tricarboxylic acid cycle. Despite a successful phase 2 study that showed significant reversal MS disability, replication of these findings fell short in phase 3 study ^[29]. These studies used composite endpoints designed to detect overall improvements in function; however, because MS disability is not only caused by demyelination but also by axonopathy and neuronal loss it is perhaps not surprising that these studies were unsuccessful ^[30].

Several small molecules with indications other than in MS are being repurposed to stimulate myelin repair. Bexarotene, a small molecule retinoic acid RXR-gamma receptor agonist that stimulate myelination in preclinical models was investigated in a phase 2 study in RMS and not only failed to meet its primary endpoint but also demonstrated poor tolerability ^[31]. A study of domperidone, a therapy used in some countries to alleviate constipation in Parkinson's disease that also stimulates prolactin secretion and therefore might promote remyelination, in SPMS failed to reach its primary endpoint ^[32]. Clemastine fumarate, an antihistamine, was identified in an in-vitro screen to promote myelin formation and showed physiologic effects consistent with remyelination in a phase 2 study of chronic optic neuropathy ^[33,34]. This study's design that targeted a specific neuroanatomic deficit known to be caused by demyelination likely contributed to its success. Clemastine fumarate is being studied in an acute optic neuritis trial (NCT02521311) and in combination with metformin, a commonly used diabetes medication that may help condition OPCs for remyelination (NCT05131828). Bazedoxifene acetate, a selective estrogen receptor modulator used in combination with conjugated estrogens to prevent postmenopausal osteoporosis, was identified in an in-vitro screen to promote myelin differentiation and is being studied in a phase 2 study in postmenopausal women with MS. Somewhat analogous to bazedoxifene in women, testosterone undecanoate is being studied as a potential remyelinating and neuroprotective therapy in men with RMS (NCT03910738).

CNM-Au8, nanocrystalline gold, catalyzes the oxidation of nicotinamide adenine dinucleotide hydride to the energetic cofactor NAD+ and may stimulate demanding cellular respiratory processes such as myelin production, potentially accounting for its remyelinating properties in preclinical models ^[35]. CNM-Au8 is being studied in a phase 2 trial of chronic optic neuropathy in RMS (NCT03536559). Thyroid hormone promotes myelination during development and in preclinical models of remyelination. Liothyronine was investigated in a phase 1 study in RMS (NCT02760056) ^[36]. Follow-up studies with this product have not been registered possibly due to concern about thyroid hormone toxicity in euthyroid participants. BIIB061 is an oral small molecule that induces OPC growth and thereby potentially promote myelin repair. A phase II, add-on study will be conducted in participants already treated with interferons and glatiramer acetate (NCT04079088).

Epstein–Barr virus

Epstein–Barr virus (EBV) infection is a well recognized MS risk factor ^{[37,38▪▪]} (Table 1). Although this is a common infection in adults and children, evidence of prior EBV infection is found in virtually every MS patient. Although EBV infection functions as a trigger for MS it remains unclear to what extent, if any, latent EBV infection contributes to MS pathogenesis ^[39]. In MS, both humoral and cellular immune responses are altered compared with unaffected controls. Children with MS have increased EBV shedding consistent with frequent EBV reactivation ^[40]. A recent study pointed to possible mechanism in which antibodies directed against EBV antigens cross-react with CNS antigens suggesting molecular mimicry as an underlying mechanism ^[41]. Autoreactive EBV-infected B cells are present in ectopic follicular like structures that are found in the meninges of MS patients and are a unique histopathological feature of the disease ^[42,43]. Latent EBV infection might contribute to MS pathogenesis and might have a role in progressive disease.

Based on these observations, autologous EBV-reactive CD8 T cells were used to treat progressive MS patients in a pilot study that showed improvement in chronic disability ^[44▪]. A larger phase 1/2 randomized, placebo-controlled clinical trial in nonrelapsing, progressive MS using heterologous, HLA-matched EBV-reactive CD8 T cells (ATA-188) is underway (NCT03283826). A single-center, phase 1 study using autologous EBV-reactive CD8 T cells in participants who experienced a first demyelinating event (clinically isolated syndrome) is underway (NCT02912897). A phase 2 study is planning to investigate whether the antiviral, tenofovir alafenamide fumarate, could improve fatigue and other outcomes in MS (NCT04880577).

New immune suppressants and immune modulators

Autoimmune demyelination in MS is mediated by T and B lymphocytes and successfully developed therapeutics target multiple immunologic processes ^[2] (Table 1). Several strategies that build upon the prior successes of immune directed therapies are in development. Teriflunomide, an inhibition of dihydro-orotate dehydrogenase (DHODH) a mitochondrial enzyme in the de novo pyrimidine synthesis pathway impairs DNA synthesis in actively proliferating T and B lymphocytes without causing cell death, is indicated in adults and children (in Europe) with relapsing MS ^[45]. However, teriflunomide has off-target activity against protein kinases, including the epidermal growth factor receptor tyrosine kinase, leading to antiproliferative side effects such as neutropenia, alopecia and diarrhea ^[46]. Vidofludimus calcium (IMU-838) is a next-generation small molecule inhibitor of DHODH with improved target specificity that may lead to a better side effect profile relative to teriflunomide ^[47]. Vidofludimus calcium is a more potent inhibitor of DHODH and is more effective at inhibiting T-cell proliferation compared with teriflunomide. Vidofludimus calcium was successfully studied in a phase 2 trial in RMS (NCT03846219) and is in development in twinned, phase 3 studies in RMS (NCT05134441, NCT05201638) and in a single trial in nonrelapsing progressive RMS (NCT05054140). Vidofludimus calcium also has antiviral activity including anticoronavirus activity, an appealing property given the Covid-19 pandemic ^[48].

Anakinra is recombinant interleukin receptor-1 antagonist and is used for treatment of deficiency of interleukin receptor-1 antagonist, refractory rheumatoid arthritis, cryopyrin-associated periodic syndromes including neonatal-onset multisystem inflammatory disease, familial Mediterranean fever and Still's disease. Anakinra is being studied in a phase 1/2 study to determine whether it has an impact on chronically inflamed brain lesions (paramagnetic rim lesions identified on 7T MRI) in MS (NCT04025554).

Imatinib mesylate is an inhibitor of the Bcr-Abl tyrosine kinase and is used as an antioncologic for several cancers. Imatinib showed benefit in a preclinical model of MS ^[49] and is being compared with methylprednisolone in a phase 2 study of MS relapses (NCT03674099). Imatinib's known toxicity may limit application.

Masitinib is a selective tyrosine kinase inhibitor targeting microglia and mast cells. A recently published phase 3 trial (NCT01433497) demonstrated clinical efficacy in slowing disease progression in primary progressive and clinically inactive SPMS. On the contrary, MRI was not performed ^[50]. A new phase 3 trial including magnetic resonance outcomes is being planned.

Foralumab (TZLS-401) is a human, anti-CD3 monoclonal antibody that modulates CD3 function without inducing lymphopenia and is delivered in a stabilized liquid form intranasally. Foralumab is under investigation in a phase 1 study of SPMS (NCT05029609).

SAR441344 is a monoclonal antibody that antagonizes the CD40 ligand, a costimulatory molecule of the immunologic synapse, and is under investigation in a phase 2 study in RMS (NCT04879628). CD40 ligand inhibition was previously studied in MS ^[51].

Simvastatin is an HMG-CoA reductase inhibitor that is proposed to have neural protective and anti-inflammatory effects in MS ^[52]. Following the success of a multicenter study in SPMS ^[53] a multicenter, placebo controlled, phase 3 trial of simvastatin in SPMS is investigating the impact of simvastatin on disability worsening (NCT03387670). It is possible that simvastatin exerts a beneficial property in SPMS through effects other and by reducing inflammation. A phase 2, placebo-controlled, study in SPMS is investigating the effect of simvastatin on a noninvasive measure of cerebral blood flow (NCT03896217).

EK-12 is a neuropeptide combination of metenkefalin (an endogenous endorphin) and tridecactide (alpha-1–13-corticotropin) and is being compared with subcutaneous interferon beta-1a in a head-to-head phase 3 study (NCT03283397). Significantly, although this study is described as a phase 3 clinical trial, there do not appear to be earlier phase studies of this neuropeptide combination in MS.

Hul001 is an antienolase monoclonal antibody that is being investigated in a phase 1 study in healthy volunteers and MS participants (NCT04540770). In addition to being an intracellular enzyme involved in glycolysis enolase is a plasminogen receptor displayed on the surface of activated monocytes and may block ENO1-bearing monocytes from CNS entry.

B-cell-targeting therapies

The profound reduction of neuroinflammation in MS by anti-CD20 monoclonal antibodies shows that B cells have a critical role in MS pathogenesis ^[2,54] (Table 1). Several approaches are in development that seek to build upon the success of B-cell depletion. Belimumab is a B-cell-activating factor that is being developed as an add-on treatment to ocrelizumab in a phase 2 study of RMS (NCT04767698). The concept behind this study is that belimumab in combination with a short course of ocrelizumab will be equally effective as ongoing ocrelizumab treatment but will be associated with less immune suppression and improved responses to pneumococcal vaccination.

Ixazomib is a site-specific proteasome inhibitor that targets plasma cells and is approved for treatment of multiple myeloma. Ixazomib is being studied to determine whether treatment will reduce the presence of oligoclonal bands in the cerebrospinal fluid in MS (NCT03783416).

Self-tolerance

Perhaps one of the most appealing concepts in MS treatment is the notion that the breach in self-tolerance which underlies autoimmune injury could be reversed through induction of antigen-specific immune tolerance (Table 1). This approach could address the underlying pathophysiology in MS without the side effects of more broadly acting immune therapies ^[55]. ANK-700 is a myelin antigen thought to be involved in MS pathogenesis, designed to restore self-tolerance by delivery to the liver where it is intended to reprogram the immune system for self-tolerance. ANK-700 is being investigated in a phase 1 study in RMS (NCT04602390).

Autologous tolerogenic dendritic cells from peripheral blood are being studied in a phase 2 clinical trial as an intravenous add-on to moderately effective treatments (NCT04530318). Tolerogenic dendritic cells are loaded with immunogenic peptides and interact with antigen-specific T lymphocytes to induce regulatory T cells. Another phase 1, single arm study will investigate the safety of autologous monocyte-derived dendritic cells tolerized with vitamin-D3 and pulsed with myelin peptides administered by intranodal injection (NCT02903537).

NeuroVax is a T cell receptor (TCR) peptide vaccine that is being studied in placebo-controlled, phase 2 clinical trials in secondary progressive (NCT02149706, NCT02057159) and pediatric MS (NCT02200718).

Microbiome

The microbial composition of the intestines interacts with dendritic cells and lymphocytes in the lamina propria (Table 1). Different commensal microorganisms can elicit proinflammatory and anti-inflammatory responses in the host. Therefore, it is possible that the gut microbiome could be involved in triggering and perpetuating MS and manipulation of the gut microbiota could be another MS therapeutic strategy ^[56]. Tauroursodeoxycholic acid (TUDCA) is a bile acid present as a minor constituent in humans but is in abundance in bears. TUDCA is used as a natural remedy in traditional Chinese medicine. TUDCA is proposed for use as a neuroprotective agent, an anti-inflammatory agent, and an apoptosis inhibitor, and may have bone density conservation and cardioprotective properties. A phase 1/2 study in progressive MS is investigating the impact of TUDCA treatment on metabolomics, gut microbiota and immunophenotyping (NCT03423121).

The association of gut microflora with MS among other neurological disorders naturally led to the hypothesis that altering the gut microflora might be beneficial in MS ^[57]. A single-arm, pilot study is investigating the safety and tolerability of oral fecal matter transplantation (FMT) in MS (NCT04096443). A large, single-arm study of FMT in multiple indications including MS is also underway (NCT04014413). Assessment of outcomes other than safety and perhaps immunology will be challenging given the uncontrolled nature of these studies. A phase 2, blinded, placebo-controlled study of allogenic versus autologous FMT that also involves preconditioning with amoxicillin/clavulanate (or matched placebo) followed by a bowel cleanse with PEGLYTE prior to FMT will assess the efficacy of FMT on MRI measures of disease activity in untreated RMS (NCT04150549).

Neural protection

Strategies aimed at preventing oligodendrocyte and neuronal injury in MS independent of antineural inflammatory mechanisms might be particularly beneficial in progressive RMS wherein neurodegeneration occurs without overt inflammatory injury ^[57] (Table 1). N-acetyl cysteine (NAC) is a glutathione precursor with antioxidant properties that was previously studied in progressive MS but found no benefit on fatigue ^[58]. NAC is being investigated in a phase 2 study of progressive MS whose goal is to show a beneficial impact on measures of brain and spinal cord atrophy (NCT05122559). Lipoic acid is a commonly used antioxidant that may have neural protective properties and is being investigated in a phase 2 study of progressive RMS to determine whether lipoic acid can help preserve ambulation and brain volume (NCT03161028).

Stem cells therapies

Eradicating memory cells in MS by intensive immune suppression with subsequent repopulation of naïve stem cells may induce sustained remission in relapsing MS ^[59] (Table 2). Several trials are following up on a large body of observational evidence studying hematopoietic stem cell transplantation as a treatment in MS ^[60–62]. Some of these studies are observational (NCT04674280, NCT05029206) or single arm with safety measures being the primary outcome (NCT03113162, NCT00716066, NCT04203017). Autologous hematopoietic stem cell transplantation (AHSCT) is being compared with alemtuzumab in a rater-blinded, single-center study (NCT03477500). Lastly, AHSCT is also being compared against best available therapy (B-cell depletion, cladribine, alemtuzumab or natalizumab) in a phase 3 randomized, rater-blinded trial in rigorously defined treatment-resistant relapsing RMS (NCT04047628). The more rigorously designed, randomized trials hopefully will provide clearly interpretable results.

Several uncontrolled, single-arm trials are studying mesenchymal stem cells either through intrathecal transplantation or intravenous infusion as a neuroregenerative or neuroprotective or treatment in MS (NCT05003388, NCT03822858, NCT04956744, NCT04943289). It is unclear what value these small, uncontrolled studies will add to the present understanding of either intrathecal or intravenous administered stem cells. Two clinical trials utilize control groups and have the potential to demonstrate therapeutic benefits. One is a phase 1/2 study using a blinded, cross-over study design will assess evoked potentials in progressive RMS (NCT04749667) and the other is a phase 2, randomized, blinded, placebo-controlled trial will assess the impact of intravenously infused adult-derived, mesenchymal stem cells on MS quality of life (NCT05116540).

CONCLUSION

A diagnosis that once carried dismal prospects for many is now a treatable disease with a much-improved prognosis. MS relapses can be almost completely eliminated and progressive disability at least partially slowed. Irreversible end-organ injury resulting in brain atrophy might be preventable with HEFT. Taken together these breakthroughs are a wonderful achievement of modern medicine and one of the most important advances in clinical neurobiology of the century. The incredible number of diverse treatments under investigation bodes well for development of better and more effective therapies. Nonetheless, there are fundamental deficits in our understanding of the molecular and cellular mechanisms that underlie disease progression. Until the precise mechanisms that cause irreversible disability are understood, it seems unlikely that definitive treatments to arrest this most vexing aspect of MS will be definitively developed. Further, our understanding of the inhibitory mechanisms that prevent neuronal CNS repair need elucidation. Thus, much work in the basic science of MS is needed to propel a next generation of treatments forward.

Acknowledgements

None.

Financial support and sponsorship

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Conflicts of interest

B.A.C.C. received personal compensation for consulting from Alexion, Atara, Autobahn, Avotres, Biogen, EMD Serono, Gossamer Bio, Horizon, Neuron23, Novartis, Sanofi, TG Therapeutics and Therini and received research support from Genentech. H.-P.H. received personal compensation for serving on steering and data monitoring committees from BayerHealthcare, Biogen, BMS Celgene, GeNeuro, Merck KG Darmstadt, Novartis, Roche, TG Therapeutics, VielaBio. M.B. received personal compensation for consulting from Novartis and Autobahn Therapeutics and research support from Biogen, Novartis, Sanofi-Genzyme, Merck, Alexion and Bristol Myers Squibb and is Research Director at the Sydney Neuroimaging Analysis Centre.